Our objective is a better understanding of vaccination-induced protection against tuberculosis (TB) in humans. This knowledge is critical for developing novel TB vaccines. Our first aim is to characterize T cell immunity following BCG vaccination of newborns. We will focus on longitudinal changes in specific CD4+ and CD8+ T cell immunity conventionally associated with protection against TB. We will test the hypothesis that regulatory CD4+ T cells are induced by BCG, and that these cells modulate specific immune outcome. Newly validated whole blood assays will be used to measure immunity in infants from South Africa, where vaccination with BCG at birth is routine, and where the TB incidence is very high. Complementary, longitudinal studies of adults vaccinated with BCG will also be performed, as larger blood volumes will allow a more comprehensive functional immune assessment. Our second aim is to identify immune components that are associated with BCG-induced protection against infant TB. To address this aim, we have already collected processed and stored blood from 5,675 10-week old South African infants, vaccinated with BCG at birth. We have subsequently identified >500 of these infants who have developed TB disease (cases), or who have remained healthy despite exposure to adults with TB (controls). We will retrieve stored blood of cases and controls, and compare conventional and regulatory immunity induced by BCG. Additionally, we hypothesize that we will identify novel genes involved in BCG-induced protection against TB, with DNA micro-array analysis. Our third aim is to determine whether the antibody response to BCG contributes to protection against TB. We will characterize this response in newborns vaccinated with BCG. We will compare the antibody response between BCG-vaccinated infants who are protected against TB, and those not protected.